Process for making a C1 -C7 aliphatic hydrocarbyl ester of an N-[2,6-di(C1 -C7 alkyl)phenyl] α-aminocarboxylic acid

ABSTRACT

Disclosed is a process for making a C 1  -C 7  aliphatic hydrocarbyl ester of an N-[2,6-(C 1  -C 7  alkyl)phenyl] α-amino-carboxylic acid from the corresponding 2,6-di(C 1  -C 7  alkyl)aniline and the corresponding chlorocarboxylic acid ester, which comprises effecting with a catalytic quantity of di(C 1  -C 7  alkyl)aniline hydrochloride the reaction of said aniline and said ester.

This invention is in the chemical arts. In particular it resides in thatpart of organic chemistry having to do with aromatic aminocarboxylicesters.

C₁ -C₇ Aliphatic hydrocarbyl esters of N-[2,6-di(C₁ -C₇ alkyl)phenyl]α-aminocarboxylic acids have utility as intermediate compounds in thepreparation of certain herbicidal esters such as those disclosed in TheNetherlands published pat. application No. 73.03363, open to publicinspection on Sept. 12, 1973.

These intermediate compounds are represented by the structural formulaI: ##STR1## in which R is C₁ -C₇ aliphatic hydrocarbyl, and R' and R"are C₁ -C₇ alkyl.

The term "hydrocarbyl" as used in this specification means a hydrocarbonradical. Accordingly, C₁ -C₇ aliphatic hydrocarbyl encompasses C₁ -C₇alkyl, C₂ -C₇ alkenyl and C₂ -C₇ alkynyl. These radicals can be straightor branched R' and R" can be the same or different. Examples of C₁ -C₇alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, and the like. Examples of C₂ -C₇ alkenyl includevinyl(ethenyl), allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methylpropenyl, and the like. Examples of C₂ -C₇ alkynylinclude acetenyl (ethynyl), 1-propynyl, 2-propynyl and the like.

These intermediate compounds in general can be made by a process inwhich the phenylamines and .[.haloalkanoic.]. .Iadd.bromoalkanoic.Iaddend.acid esters corresponding to them are reacted in an inertliquid medium containing a base such as potassium hydroxide or the like.The desired reaction is depicted by the equation: ##STR2## X in theabove formulas is .[.halo. However, the resulting reaction mixture has anumber of impurities such as, for example, the dicarboxylic acid esterof the formula II: ##STR3## and products resulting from saponificationof the ester moiety. Consequently, isolation of the desired compound inthe desired degree of purity if difficult to obtain, and the yield ofthe desired compound is lower than desired..]. .Iadd.bromo. When theester reactant is a chloroalkanoic acid ester, the reaction depicted bythe equation does not go. .Iaddend.

.[.This invention minimizes these disadvantages of the foregoingprocess..].

.Iadd.This invention provides a process in which the phenylamine and thechloroalkanoic acid ester react. .Iaddend.

In brief, the process of this invention comprises effecting reaction ofthe corresponding phenylamine and the .[.haloalkanoic.]..Iadd.chloroalkanoic .Iaddend.acid ester with a catalytic quantity of2,6-di(C₁ -C₇ alkyl)aniline hydrochloride. In the preferred embodimentof this invention the 2,6-di(C₁ -C₇ alkyl)aniline hydrochloride is thehydrochloride of the phenylamine reactant.

In the preferred practice of the process of this invention thephenylamine reactant and the aniline hydrochloride are admixed and the.[.haloalkanoic.]. .Iadd.chloroalkanoic .Iaddend.acid ester is slowlyadmixed with the resulting mixture.

As above stated, the quantity of 2,6-di(C₁ -C₇ alkyl)anilinehydrochloride employed as catalyst is a catalytic quantity. In generalsatisfactory results are obtained when the concentration of thehydrochloride is about 0.5-5% by weight of the phenylamine reactant.

In the preferred practice of the process the catalyst can be added assuch to the phenylamine reactant or, particularly in the embodiment inwhich the 2,6-di(C₁ -C₇ alkyl)aniline hydrochloride is the hydrochlorideof the phenylamine reactant, it can be formed in situ in the phenylaminereactant by admixing with the reactant a quantity of hydrochloric acidequivalent to the desired catalyst concentration.

The reaction can be carried out neat or in the presence of an inertliquid reaction medium for better control of the reaction temperature.Examples of such a liquid reaction medium include benzene, toluene,xylene, and the like.

The preferred reaction temperature range is 100°-250° C. However, higherand lower temperatures are within the broader concepts of thisinvention. On the other hand, the higher the reaction temperature, thehigher is the concentration of impurities such as the dicarboxylic acidester.

Although in the usual practice of the process of this invention thereaction is carried out at atmospheric pressure, under the broaderconcepts of this invention higher and lower pressures can be employed.

The reaction time is generally in the range from about 15 minutes toabout 10 hours. Lesser and greater reaction times, however, are withinthe broader concepts of this invention. On the other hand, in general areaction time of less than about 15 minutes can result in less than apractical conversion of the phenylamine and the haloalkanoic acid esterto the desired product, while in general a reaction time greater thanabout 7 hours can result in substantial concentrations of impurities.

After completion of the reaction the reaction mixture can be used as inthe reaction of the intermediate compound to form the desired end usecompound such as one of those disclosed in the cited published patentapplication, or the reaction mixture can be treated to isolate theintermediate compound with the desired degree of purity. Such atreatment in one embodiment of the invention comprises admixing thereaction mixture with an inert nonpolar solvent (for example, benzene,toluene, xylene, and the like) for the intermediate compound in quantitypreferably sufficient to dissolve substantially all the intermediatecompound, if such is not already present, separating solid anilinehydrochloride, if any, from the resulting solution, washing the solutionwith a weak aqueous solution of an inorganic acid to remove unreactedamine, and removing the solvent by distillation or evaporation.

The best mode now contemplated for carrying out the process of thisinvention is illustrated by the following examples of specificembodiments thereof. This invention is not limited to these embodiments.In these examples all percentages are by weight unless otherwiseindicated, all parts by weight are indicated by w, all parts by volumeare indicated by v, and each part by weight w bears the samerelationship to each part by volume v as the kilogram does to the liter.

EXAMPLE 1

This example illustrates the synthesis of N-(2,6-diethylphenyl)glycineethyl ester by a specific embodiment of the inventive process in whichthe reaction is carried out neat or without an inert liquid reactionmedium.

A mixture of 2,6-diethylaniline (30 w) and 2,6-diethylanilinehydrochloride (1 w) is stirred and heated to 180° C. Ethyl chloroacetate(12.2 w) is added dropwise over 15 minutes to the mixture and thetemperature of the reaction mixture is maintained at 180° C. for 15minutes after completion of the addition of the ethyl chloroacetate.

After cooling the reaction mixture to room temperature (20°-25° C.)benzene (100 v) is admixed with the reaction mixture, and the resultingmixture is filtered. The filtrate is washed twice with water (35 v eachtime), 4 times with a 10% aqueous solution (35 v each time) of H₂ SO₄,and once with water (35 v). The washed solution is dried over sodiumsulfate and the solvent removed therefrom by evaporating to drynessunder reduced pressure. The residue (18.9 w) consists essentially ofN-(2,6-diethylphenyl)glycine ethyl ester. A typical concentration of theester in the residue as determined by liquid chromotography is 80%.

EXAMPLE 2

This example illustrates the preparation of N-(2,6-diethylphenyl)glycineethyl ester by another specific embodiment of the inventive process inwhich the reaction is carried out in an inert liquid reaction medium.

A mixture of 2,6-diethylaniline (268 w), 2,6-diethylanilinehydrochloride (5 w) and toluene (72 w) is heated to 158° C. Ethylchloroacetate (98 w) is added all at once and the resulting reactionmixture established and maintained with stirring at 148°-150° C. for 6.5hours.

The reaction mixture is then cooled to room temperature (20°-25° C.),toluene (165 w) is added, and the resulting diluted mixture filtered toremove solid 2,6-diethylaniline hydrochloride. The resulting filtrate iswashed at 80° C. twice with water (400 v each time) at at roomtemperature (20°-25° C.) 7 times with a 10% aqueous solution (120 v eachtime) of H₂ SO₄, and once with water (200 v). The washed solution isdried over magnesium sulfate, and the toluene removed by evaporation todryness under reduced pressure. The residue (135.8 w) consistsessentially of N-(2,6-diethylphenyl)glycine ethyl ester.

A typical analysis of the residue by liquid chromotography is 92%N-(2,6-diethylphenyl)glycine ethyl ester and 2.9%N-bis(carbethoxymethyl)-2,6-diethylaniline with impurities at a minimum.

EXAMPLE 3

This example illustrates the preparation of N-(2,6-diethylphenyl)glycineallyl ester by a specific embodiment of the process of this invention.

2,6-Diethylaniline (11.6 w), 2,6-diethylaniline hydrochloride (0.4 w)and dry toluene (3.1 w) are stirred together. While the resultingmixture is reflexed at 160° C. allyl chloroacetate (10.5 w) is addedslowly thereto. The resulting reaction mixture is refluxed at 145° C.for 2 hours and then cooled to 20°-25° C. Toluene (75 v) is admixed withit. Solids in the diluted reaction mixture are separated by filtrationand washed with toluene. The wash liquid is mixed with the filtrate andthe solution is washed once with water (40 v), once with a 10% aqueoussolution (40 v) of H₂ SO₄, and 3 times with water (40 v each time). Thewashed solution is dried over MgSO₄, overnight, the MgSO₄ is removed byfiltration, and the solvent is removed from the filtrate bydistillation. The residue (7.0 w) is typically a dark brown resin whichconsists essentially of N-(2,6-diethylphenyl)glycine allyl ester withimpurities at a minimum.

EXAMPLE 4

This example illustrates the preparation ofN-(2-ethyl-6-methylphenyl)glycine allyl ester by a specific embodimentof the process of this invention. 2-Methyl-6-ethylaniline (10.5 w),2,6-diethylaniline hydrochloride (0.4 w) and dry toluene (3.1 w) arestirred together. While the resulting mixture is refluxed at 160° C.,allyl chloroacetate (10.5 w) is added slowly. After addition of theallyl chloroacetate has been completed, the resulting reaction mixtureis refluxed at 155°-162° C. for 5 hours. Typically a few solids mayappear about 1 hour after completion of the addition of thechloroacetate, but they tend to disappear by the end of the 5 hourreflux period. The reaction mixture is cooled to 20°-25° C. and allowedto sit overnight. Toluene (75 v) is added to the reaction mixture. Theresulting solution is washed once with water (50 v), twice with a 10%aqueous solution (50 v each time) of H₂ SO₄, and three times with water(50 v each time). The washed solution is dried over MgSO₄, the MgSO₄ isremoved by filtration, and the solvent is removed by distillation. Theresidue (4.7 w) is typically a dark brown liquid. It consistsessentially of N-(2-ethyl-6-methylphenyl)glycine allyl ester with aminimum of impurities.

EXAMPLE 5

This example illustrates the preparation of N-(2,6-diethylphenyl)glycine1-butyn-3-yl ester by a specific embodiment of the process of thisinvention.

Stirred together at reflux (140° C.) are 2,6-diethylaniline (25.3 w),2,6-diethylaniline hydrochloride (1.0 w), and dry toluene (8 w) to forma mixture. 1-Butyn-3-yl chloroacetate (25.0 w) is admixed slowly withthe mixture, and the resulting reaction mixture is refluxed 2 hours at155° C. The reaction mixture is cooled to 20°-25° C. and toluene (150 v)is added. The diluted mixture is filtered to remove solids and thefiltrate is washed once with water (100 v), once with a 10% aqueoussolution (100 v) of H₂ SO₄, and three times with water (100 v eachtime). The washed solution is dried over MgSO₄ and, after removal of theMgSO₄ by filtration, the toluene is removed by distillation. The residue(22.3 w) is typically an amber liquid. It consists essentially ofN-(2,6-diethylphenyl)glycine 1butyn-3-yl ester with a minimum ofimpurities.

EXAMPLE 6

This example illustrates the synthesis ofN-(2-ethyl-6-methylphenyl)glycine 1-butyn-3-yl ester by a specificembodiment of the invention process.

Stirred together at reflux (140° C.) are 2-ethyl-6-methylaniline (22.95w), 2,6-diethylaniline hydrochloride (1.0 w), and dry toluene (8 w). Tothis mixture is slowly added 1-butyn-3-yl chloroacetate (25.0 w). Theresulting reaction mixture is refluxed 2 hours, and then cooled to20°-25° C. After addition of toluene (150 v) to the reaction mixture,the diluted reaction mixture is filtered to remove solids, and thefiltrate is washed with water (100 v), a 10% aqueous solution (100 v) ofH₂ SO₄, and 3 times with water (100 v). After drying the washed solutionover MgSO₄, and filtering to remove the MgSO₄, the toluene is removed bydistillation. The residue (10.0 w) is typically an amber liquid. Itconsists essentially of N-(2-ethyl-6-methylphenyl)glycine 1-butyn-3-ylester with a minimum of impurities.

Thus, this invention provides a process for reacting the phenylamine and.[.haloalkanoic.]. .Iadd.chloroalkanoic .Iaddend.acid estercorresponding to an intermediate compound of the above formula I toobtain said intermediate compound with a minimum of impurities.

Other features, advantages and specific embodiments of this inventionwill become readily apparent to those exercising ordinary skill in theart after reading the foregoing disclosures. In this connection, whilespecific embodiments of this invention have been described inconsiderable detail, variations and modifications of these embodimentscan be effected without departing from the spirit and scope of theinvention as disclosed and claimed.

The expression "consisting essentially of" as used in this specificationexcludes any unrecited substance at a concentration sufficient tosubstantially adversely affect the essential properties andcharacteristics of the composition being defined, while permitting thepresence of one or more unrecited substances at concentrationsinsufficient to substantially adversely affect said essential propertiesand characteristics.

I claim:
 1. A process for synthesizing a C₁ -C₇ aliphatic hydrocarbylester of an N-[2,6-di(C₁ -C₇ alkyl)phenyl] α-aminocarboxylic acid fromthe corresponding 2,6-di(C₁ -C₇ alkyl)aniline and the corresponding.[.chlorocarboxylic.]. .Iadd.chloroacetic .Iaddend.acid ester, whichcomprises effecting with a catalytic quantity of2,6-.Iadd.di.Iaddend.(C₁ -C₇ alkyl)aniline hydrochloride reaction ofsaid aniline and said ester.
 2. A process according to claim 1 in whichsaid reaction is carried out at 100°-250° C. for a period of time fromabout 15 minutes to about 5 hours, and said catalytic quantity is about0.5-5% by weight of said aniline.
 3. A process according to claim 2 inwhich the reaction is carried out neat.
 4. A process according to claim2 in which the reaction is carried out in an inert liquid reactionmedium.
 5. A process according to claim 4 in which said hydrochloride isthe hydrochloride salt of said aniline reactant.
 6. A process accordingto claim 5 in which said aniline is 2,6-diethylaniline.
 7. A processaccording to claim 6 in which said chlorocarboxylic acid ester is ethylchloroacetate.